Process for the production of lyophilized effervescent pharmaceutical compositions

ABSTRACT

LYOPHILIZED EFFERVESCENT PHARMACEUTICAL COMPOSITIONS WHICH DISSOLVE RAPIDLY IN WATER WHILE HAVING IMPROVED MECHANICAL STRENGTH AND RESISTANCE TO ATMOSPHERIC MOISTURE ARE MADE BY LYOPHILIZING EFFERVESCENT MATERIALS BELOW 0*C. IN ADMIXTURE WITH LYOPHILIZATION ADJUVANTS SUCH AS SUCROSE AND LACTOSE.

United States Patent Int. Cl. A611: 9/00 US. Cl. 424-44 3 Claims ABSTRACT OF THE DISCLOSURE Lyophilized effervescent pharmaceutical compositions which dissolve rapidly in water while having improved mechanical strength and resistance to atmospheric moisture are made by lyophilizing effervescent materials below 0 C. in admixture with lyophilization adjuvants such as sucrose and lactose.

This is a division of application Ser. No. 28,550 filed Apr. 14, 1970 now abandoned.

This invention relates to the tical compositions.

It is well known that lyophilised products always have a fragile structure and are furthermore generally extremely hygroscopic. These two properties make them diflicult to handle in an environment of normal humidity and make it necessary to use perfectly sealed packages for them.

This invention provides a process for the production of pharmaceutical compositions which have been dehydrated or desolvated by lophilisation, and which are capable either of resuming their original form if solvent is provided, or of dissolving rapidly and completely in water. The new process furthermore makes it possible to lessen the two disadvantages described above by combining the medicament to be lyophilised with a lyophilisation adjuvant which imparts improved mechanical strength to the lophilised product and slows down the moisture uptake.

The process of the present invention comprises mixing a medicament, in the presence of water with at least one lophilisation adjuvant chosen from: (a) non-toxic colloids, polysaccharides and polymers of high molecular weight capable of yielding colloidal solutions, and (b) soluble, edible, crystallisable, extenders, and lyophilising the mixture obtained.

The lyophilisation adjuvants used in the new process must have such physical properties that their addition cannot interfere with the proper course of the lyophilization operation. Thus, they must not lower the freezing point of the material to be lyophilised to a level where melting would occur during the lyophilization. As these substances must be considered to be excipients for the pharmaceutical compositions, it is essential for them to have no effect on the medicament and to be physiologically innocuous.

Suitable materials are: (a) colloids, polysaccharides of high molecular weight, and high polymers which can yield colloidal solutions, especially gum arabic, alginates and pectinates, polyvinylpyrrolidone, polyethylene glycols, and carboxymethylcellulose; and (b) soluble, edible and crystallisable extenders, especially lactose, glycine, mannitol, sorbitol, glucose, and sucrose. Amongst the latter lactose, which normally contains one molecule of water, loses this during the lyophilisation and can, as a result, play the role of a dehydrating agent in the lyophilised product.

These additional substances can be used individually or in mixtures. Harmoniously calculated proportions of these production of pharmaceusubstances added to a solution of the material to be lyophilised make it possible to obtain a lyophilised product which is consistent, stable under normal ambient conditions, and entirely soluble and devoid of any toxicity (other than any toxicity of the medicament itself).

Variations in the amount of the lyophilization adjuvant make it possible to achieve any desired degree of hardness and solubility of the lyophilised product.

Medicaments of all kinds can be incorporated into mixtures to be lyophilized in accordance with the invention, e.g. water-soluble medicines, insoluble medicines dispersed as a colloidal suspension or emulsions, and also insoluble, undispersed medicines.

The lyophilised product obtained can be mechanically divided into pieces of well-defined shape and volume, which can be packed individually or in groups.

The pharmaceutical compositions obtained by the new process can be classified alongside effervescent, entirely soluble tablets while avoiding the use of large amounts of alkaline excipients, or alongside drinkable ampoules, having an advantage in cost price, or alongside any liquid form, having a definite advantage of lower volume and weight for a given dosage and showing great stability and excellent storage characteristics.

In the new process, the lyophilization adjuvant is added to the material to be lyophilised in the presence of a small amount of water, at ordinary temperature, and the resulting solution or paste is subsequently lyophilized in a manner known per se. If the mixture to be lyophilized is too liquid, because of the choice of the proportions of the constituents or for other reasons, and a separation takes place during mixing, the mixture is frozen with continuous stirring and when a pasty consistency has been achieved the mixture is spread on the previously cooled plates of the lyophilisation apparatus.

In one embodiment of the new process, the mixture to be lyophilised is converted into a foam and is stabilised with a block polymer of ethylene oxide, propylene oxide and ethylene glycol of molecular weight between 7500 and 8250, of the formula:

(where x, y, and z are integers) in which the (C3H60)y portion has a molecular weight of 1500 to 1800 and the (C H O) portion represents -90% by weight of the polymer. This embodiment is particularly advantageous for the preparation of a lyophilised composition containing vitamin C. It is all the more unexpected because it is known that vitamin C cannot be lyophilised by itself but melts, regardless of the lyophilisation conditions, forming a varnish on the cooled surfaces of the lyophilization apparatus, without a continuous solution, thereby resisting lyophilisation.

Another embodiment of the invention relatesto the preparation of effervescent pharmaceutical compositions. Etferverscent pharmaceutical compositions have hitherto been prepared by a dry method, by combining a medicament in the anhydrous form with an effervescent mixture consisting of two anhydrous powders, one containing nontoxic organic acid such as e.g. citric acid, tartaric acid, or ascorbic acid and the other containing a weak mineral base particularly (carbonate or bicarbonate) such as an alkali metal or alkaline earth metal carbonate or bicarbonate, especially neutral sodium carbonate or sodium bicarbonate, calcium carbonate, or magnesium carbonate. The mixture thus obtained is shaped into tablets and stored with exclusion of moisture. When introduced into water, it dissolves, causing an effervescence due to copious evolution of carbon dioxide.

The process of this invention for making such compositions is a wet process, in which the constituents of the effervescent mixture are added to the mixture to be lyophilised, at a temperature below C. sufficient to pre- TABLE I vent any reaction between the constituents of the effervescent mixture, and the paste obtained is subsequently lyo- Number philised. Small containers 1 2 3 4 6 Such a process has many advantages. It makes it pos- Liver extract, sible to obtain lyophilised composrtlons WhlCh. are comg y s" pletely soluble, because no insoluble excipients used as $f lubricants for tablet making (talc, stearate and the like) Wat r, m1 15 Weight after lyophilisation, g 2.30 61 61 63.30 63. 30

are employed. Desiccation by lyophilisation yields dryer products than those obtained by conventional drying proc- 1Q esses without reaching temperatures which present the danger of altering any heat-labile active medicaments present in the composition.

The invention is illustrated by the following examples.

The temperature and pressure conditions used during the lyophilisation are given in Table II below. r After the lyophilisation, the small containers are EXAMPLE 1 Weighed at intervals which during the first six hours are initially closely spaced, and the moisture uptakes are expressed, in Table III below, in milligrams of water taken In this example, the manufacture of a medicine based up by the contents of the small containers, the ad acent on liver extract is described. The same process can also b applied t th di column giving the percentage of water in the product.

The starting point is a commercially available liver ex- The exammatlon of the results Shows that du1'1I 1g the tract for d ink bl preparations, 1:25 in the f of a first hours the moisture uptake of the liver extract in lacsoft extract containing 82% of lid tose (No. 5) or in glycine (No. 4) is very slight relative to S ll 1 hi i i containers, f parallelepiped Shape (that of) the lyophilised extract (No. 1), because the 2.30 and of size 5 cm. x 5 cm. x 3 cm., made of an aluminium 2 Of dry extract only take P 11 13- after 4 hours foil of 50 microns thickness, are used. The surface which tose and 52 after 4 hours in glycine (*I while is in Conta t ith i i h 5 5:25 a The Small the lyophilised extract (No. 1) had taken up 131 mg., o t i b d 1 to 5 fill d as f representing 5.7% of water, as against 0.153% for the mixture of lactose liver and 0.2% for the mixture of No. 1-Solution: G, glycine liver.

Liver extract, 1:25 4 This shows that the very hygroscopic products are pro- Water to 50 ml. tected against a rapid moisture uptake, which allows them to be handled without taking many precautions and fur- No. 2-Homogeneous paste obtained by triturating in a thermore their low water content ensures that they store mortar: G. excellently. Furthermore, lactose has proved superior to Glycine 60 glycine. Gum arabic in powder form 1 The measurements of the mechanical strength of the lyo- Wat 15 1, philised products were carried outwith a needle penetrometer usually employed for measuring the hardness of No. 3-The same paste as 2, in which the glycine is retablets. An increasing force is applied to the material over placed by lactose. a constant surface area and the force required for break- No. 4The same paste as 2, but with 4 g. of liver extract age or for penetration of the needle is measured.

dissolved in the 15 ml. of water. For the products No. 1 to No. 5 quoted above, the. fol- No. 5The same paste as 3, to which 4 g. of liver extract lowing hardnessess were found:

have been added.

No. 1-too low, not measurable Table I below summarise the composition of the con- No. 25.5 to 7 kg.

tents of the small containers before lyophilisation and No. 3-8 to 12 kg. gives the net dry weights of the products obtained after No. 4-2 to 3 kg. lyophilisation. No. 5-6 to 7 kg.

TABLE IL-TEMPERAIURE AND PRESSURE CONDITIONS USED DURING THE LYOPHILISATION PROCESS Time in hours- 0 2 3 4 5 6 20 22 24 25 27 28 29 30 31 44 46 Temperature of the material v 1 in, C +20 +5 0 4 24 30 24 22 15 -1 +22 +25 +27 +28 +30 +44 +37 ressurein, mm. of Hg 760 760 760 760 2X10 2X10- 1.3)(10- 1.3X10' 1.3)(10- 1.3)(10- 10- 10' 10- 10 3X10- 3X10- TABLE III.-WATER UPTAKE OF THE VARIOUS SAMPLES AS A FUNCTION 01 TIME Weight of the finely anilised product No. 1, liver N0. 2. glycine No. 3, lactose N0. 4, glycine No. 5, lactose alone 2.30 g. 61 g. 61 g. plus liver 63.3 g. plus liver 63.3 g. Mg. Percent Mg. Percent Ma. Percent Mg. Percent Mg. Percent Mg. Mg 15 minutes 20 0 87 13 0 021 13 0.021 20 0 031 16 0 025 7 3 34 I 48 23 0 038 23 0.038 37 0 058 27 0 042 14 4 45 1 06 30 0 049 30 0.049 51 0 072 36 0 057 21 6 55 2 4 36 0 059 37 0 060 0 09 44 0 070 24 7 94 4.1 58 0 005 59 0 091 92 0 145 68 0 107 34 9 112 4.9 68 0 112 71 0.116 107 0 17 82 0 129 39 11 131 5. 7 78 0 128 86 0.14 130 0 20 97 0 153 52 11 153 6. 88 0 144 0.164 152 0 24 116 1 183 64 16 164 7. 1 92 0 151 102 0.167 165 0 26 126 0 20 73 249 10. 9 108 0 178 154 0.252 285 0 45 235 0 37 177 81 72 hours 317 13. 8 114 0. 188 0. 270 387 0 61 334 0 52 273 69 Water uptake by the liver extract in the glycine (No. 4, No. 2). "Water uptake by the liver extract in the lactose (No. 5, N0. 3).

EXAMPLE 2 The process described in Example 1 is repeated, but replacing the gum arabic by each of the following excipients.

The experiments were carried out adding the amount of polymer indicated below to 250 g. of lactose or of glycine:

G. Polyethylene glycol, M.W.-=20,000 15 Polyethylene glycol, M.W.=6,000 15 Polyvinylpyrrolidone Carboxymethylcellulose 2.5 Sodium alginate 1.25 Guaranate AC 110 1.25

All these experiments proved satisfactory and gave results of the same order as those mentioned in Example 1 above.

EXAMPLE 3 The process of Example 1 is repeated, but replacing the lactose and the glycine by other substances such as: glucose, sucrose and mannitol, either by themselves or mixed with the two preceding Substances. The experiments carried out with or without gum arabic gave good results. Table IV below gives in grams the quantities used in the various experiments.

This example describes the preparation of a medicine based on vitamin C.

Vitamin C cannot be lyophilized alone since it melts regardless of the lyophilization conditions, forming a varnish on the lyophilization surfaces. The present invention overcomes this difliculty by creating a foam in the mixture which results in the formation of small channels, which permit lyophilization, and introducing the vitamin C into the mixture at the last moment so that virtually no dissolution occurs.

Experiments carried out on a mixture of lactose, glycine and gum arabic and on a mixture of glycine and gum arabic did not permit utilization of over 0.05 g. of vitamin C, regardless of the technique employed in foaming.

However, on using the following mixture: glycine-i-gum arabic-l-RC 102 (Pluronic F 68) in which the RC 102 (a block polymer of ethylene oxide, propylene oxide and ethylene glycol) serves as a foam stabiliser, it proved possible successfully to lyophilise doses of vitamin C of 0.100 g., 0.250 g. and 0.500 g.

TABLE V.FORMULAT1ONS PRODUCED Vitamin C, g 0. 0. 250 0.500 Glycine, g 1. 100 1.100 1.100 Gum arabic, 0. 06 0.00 0.06 RC 102 platelets, 0. 05 0. 05 0. 05 Deionized water, ml 0.3 0. 3 0. 3

For one piece of approximate weight, g. 1.31 1.46 1. 71

EXAMPLE 5 This example describes the preparation, by lyophilisation, of a medicine based on arginine acid aspartate in an effervescent form. The following two mixtures A and B are separately prepared in a mortar:

The two mixtures A and B are separately cooled until they reach a temperature of 4" C. or below. A is then rapidly mixed with B while continuing cooling. The paste is spread as an approximately 1 cm. thick layer on metal plates and frozen at 20 C., and the material is lyophilised. The lyophilised product is then cut into pieces each weighing 5 g. Each piece contains 1 g. of arginine acid aspartate and dissolves very rapidly in water.

I claim:

1. The process for the preparation of an effervescent pharmaceutical composition in which an alkali metal or alkaline earth metal carbonate or bicarbonate is mixed with a nontoxic organic acid which comprises combining a first mixture comprising the bicarbonate or carbonate, sucrose and lactose with sufficient water to form a paste, combining a second mixture comprising the organic acid, sucrose and lactose with suflicient water to form a second paste, cooling said first and second pastes to a temperature sufficiently below 0 C. to prevent any reaction, mixing said cooled pastes and rapidly lyophilizing the resultant mixture.

2. Process according to claim 1 in which the organic acid is citric, tartaric, or ascorbic acid, and, as base, an alkali metal carbonate, or alkaline earth metal carbonate.

3. Process according to claim 1 in which the material to be lyophilised includes arginine acid aspartate, the organic acid is citric acid and the bicarbonate is sodium bicarbonate.

References Cited SAM ROSEN, Primary Examiner 

